Exome Sequencing for Prenatal Diagnosis in Nonimmune Hydrops Fetalis.

BACKGROUND: The cause of most fetal anomalies is not determined prenatally. Exome sequencing has transformed genetic diagnosis after birth, but its usefulness for prenatal diagnosis is still emerging. Nonimmune hydrops fetalis (NIHF), a fetal abnormality that is often lethal, has numerous genetic causes; the extent to which exome sequencing can aid in its diagnosis is unclear. METHODS: We evaluated a series of 127 consecutive unexplained cases of NIHF that were defined by the presence of fetal ascites, pleural or pericardial effusions, skin edema, cystic hygroma, increased nuchal translucency, or a combination of these conditions. The primary outcome was the diagnostic yield of exome sequencing for detecting genetic variants that were classified as either pathogenic or likely pathogenic according to the criteria of the American College of Medical Genetics and Genomics. Secondary outcomes were the percentage of cases associated with specific genetic disorders and the proportion of variants that were inherited. RESULTS: In 37 of the 127 cases (29%), we identified diagnostic genetic variants, including those for disorders affecting the RAS-MAPK cell-signaling pathway (known as RASopathies) (30% of the genetic diagnoses); inborn errors of metabolism and musculoskeletal disorders (11% each); lymphatic, neurodevelopmental, cardiovascular, and hematologic disorders (8% each); and others. Prognoses ranged from a relatively mild outcome to death during the perinatal period. Overall, 68% of the cases (25 of 37) with diagnostic variants were autosomal dominant (of which 12% were inherited and 88% were de novo), 27% (10 of 37) were autosomal recessive (of which 95% were inherited and 5% were de novo), 1 was inherited X-linked recessive, and 1 was of uncertain inheritance. We identified potentially diagnostic variants in an additional 12 cases. CONCLUSIONS: In this large case series of 127 fetuses with unexplained NIHF, we identified a diagnostic genetic variant in approximately one third of the cases. (Funded by the UCSF Center for Maternal-Fetal Precision Medicine and others; ClinicalTrials.gov number, NCT03412760.).

Nonimmune hydrops fetalis: identifying the underlying genetic etiology.

PURPOSE: Numerous etiologies may lead to nonimmune hydrops fetalis (NIHF), and the underlying cause often remains unclear. We aimed to determine the proportion of NIHF cases in which the etiology was clearly determined in a large, contemporary, and diverse cohort, as well as to describe the etiologies with a focus on genetic causes. METHODS: Retrospective review of NIHF cases between 2015 and 2017 from the five University of California Fetal-Maternal Consortium sites. Singleton pregnancies with prenatally diagnosed NIHF were included, and cases with maternal alloimmunization were excluded. Cases were categorized as being of confirmed, suspected, or unknown etiology. RESULTS: Sixty-five NIHF cases were identified. Forty-six percent (30/65) remained of unknown etiology, while 9.2% (6/65) had a suspected etiology and 44.6% (29/65) were of confirmed etiology. Among confirmed cases, 11 resulted from aneuploidy; 7 from fetal structural anomalies; 2 each from fetal arrhythmia, Noonan syndrome, and generalized lymphatic dysplasia; and 1 each from arthrogryposis, parvovirus, neonatal alloimmune thrombocytopenia, fetal goiter, and Kasabach-Merritt syndrome. CONCLUSION: In this contemporary, multicenter study, the cause of prenatally diagnosed NIHF was confirmed in only 44% of cases, and a genetic etiology was found in only 25% of those that received standard of care genetic testing.

Multi-Institutional Practice-Patterns in Fetal Congenital Heart Disease Following Implementation of a Standardized Clinical Assessment and Management Plan.

Background Prenatal diagnosis of congenital heart disease has been associated with early-term delivery and cesarean delivery (CD). We implemented a multi-institutional standardized clinical assessment and management plan (SCAMP) through the University of California Fetal-Maternal Consortium. Our objective was to decrease early-term (37-39 weeks) delivery and CD in pregnancies complicated by fetal congenital heart disease using a SCAMP methodology to improve practice in a high-risk and clinically complex setting. Methods and Results University of California Fetal-Maternal Consortium site-specific management decisions were queried following SCAMP implementation. This contemporary intervention group was compared with a University of California Fetal-Maternal Consortium historical cohort. Primary outcomes were early-term delivery and CD. A total of 496 maternal-fetal dyads with prenatally diagnosed congenital heart disease were identified, 185 and 311 in the historical and intervention cohorts, respectively. Recommendation for later delivery resulted in a later gestational age at delivery (38.9 versus 38.1 weeks, P=0.01). After adjusting for maternal age and site, historical controls were more likely to have a CD (odds ratio [OR],1.8; 95% CI, 2.1-2.8; P=0.004) and more likely (OR, 2.1; 95% CI, 1.4-3.3) to have an early-term delivery than the intervention group. Vaginal delivery was recommended in 77% of the cohort, resulting in 61% vaginal deliveries versus 50% in the control cohort (P=0.03). Among pregnancies with major cardiac lesions (n=373), vaginal birth increased from 51% to 64% (P=0.008) and deliveries ≥39 weeks increased from 33% to 48% (P=0.004). Conclusions Implementation of a SCAMP decreased the rate of early-term deliveries and CD for prenatal congenital heart disease. Development of clinical pathways may help standardize care, decrease maternal risk secondary to CD, improve neonatal outcomes, and reduce healthcare costs.

The Extended Fetal Cardiac Examination: Is It Feasible in a High-Risk Practice?

The aims of this study were to demonstrate the feasibility of obtaining additional cardiac views as proposed on an extended fetal cardiac examination and to see if there was any variation in individual components of that examination stratified by sonographer training, patient body habitus, or equipment. We retrospectively reviewed 200 consecutive detailed second-trimester high-risk fetal obstetric sonograms that included additional extended cardiac views. We analyzed the percentage of the time individual views were obtained, with variation based on (1) a sonographer with greater than 3 years of training compared with a group with 6 to 12 months of training, (2) 2 different ultrasound units, and (3) different body mass indices. Overall, the highest rate of visualization was achieved with the 4-chamber view (98.2%), whereas the 3-vessel tracheal view had the lowest percentage of visualization (40.2%), among the less experienced sonographers. Differences in successful completion of the extended cardiac views were not statistically different between the sonographer with a level of training greater than 3 years as compared with those with 6 to 12 months' training except for the 3-vessel tracheal view (P < 0.001). There is no statistically significant difference in our ultrasound equipment, when considering only inexperienced sonographers. Increasing body mass index had an inverse relationship with obtaining the components of the detailed cardiac examination. Using state-of-the-art ultrasound equipment and with focused additional training of obstetric sonographers, the majority of extended cardiac views can be obtained. There are exceptions.

Vaginal vs. cesarean delivery for preterm breech presentation of singleton infants in California: a population-based study.

OBJECTIVE: To examine the morbidity and mortality associated with vaginal breech delivery (VBD) of premature, low-birth-weight (LBW) (< 2.5 kg) newborns as compared to delivery by cesarean section. STUDY DESIGN: A retrospective cohort study of singleton, preterm (< 37 weeks), LBW, nonanomalous newborns in California (January 1, 1991-December 31, 1999) was performed. Neonatal morbidity and mortality by route of delivery were compared. RESULTS: Overall, 14,417 LBW, preterm, breech newborns were delivered (14% vaginally and 86% by cesarean). There were 150,570 LBW, preterm, cephalic newborns, of whom 82% were delivered vaginally. VBD of LBW newborns in nulliparous women was associated with increased neonatal mortality in newborns weighing 500-1,000 g (OR 11.7; 95% CI 7.9, 17.2), 1,001-1,500 g (OR 17.0; 95% CI 6.8, 42.7), 1,501-2,000 g (OR 7.2; 95% CI 2.4, 21.4), and 2,001-2,500 g (OR 6.6; 95% CI 2.1, 21.2) as compared with breech delivery by cesarean in nulliparous women. Birth trauma was increased in VBD of newborns weighing 1,500-2,000 g (OR 3.8; 95% CI 1.4, 10.1) and 2,001-2,500 g (OR 4.5; 95% CI 2.6, 7.9) as compared to breech delivery by cesarean in nulliparous women. Birth asphyxia was increased in breech newborns weighing 2,001-2,500 g (OR 3.5; 95% CI 2.2, 5.6) delivered vaginally in nulliparous women as compared to cephalic vaginal deliveries. CONCLUSION: VBD of the preterm, LBW newborn is associated with significantly increased neonatal mortality as compared to cesarean section at similar birth weights. Birth trauma (> 1,500 g) was greater with VBD as compared to breech delivery by cesarean, and asphyxia (> 2,000 g) was greater with VBD as compared to cephalic vaginal delivery, suggesting that cesarean delivery may be a safer route of delivery for preterm breech fetuses.

Vaginal versus cesarean delivery for breech presentation in California: a population-based study.

OBJECTIVE: To examine the population-based pregnancy outcomes associated with vaginal breech delivery. METHODS: A retrospective, population-based cohort study of all term (greater than 37 weeks' gestation), normal birth weight (2.5-3.8 kg), nonanomalous newborns in California, from January 1, 1991 to December 31, 1999 was performed. Neonatal mortality and major neonatal morbidity were compared by route of delivery for cephalic (3,271,092) and breech (100,730) presentations. RESULTS: More than 3.2 million singleton term newborns were identified during the study period, with 100,667 (3%) in breech presentation at the time of delivery. Of these, 4952 women (4.9%) had vaginal breech delivery, whereas 60,418 women delivered by cesarean without labor, and 35,297 women underwent cesarean in labor. Breech vaginal delivery in nulliparous women was associated with increased neonatal mortality (odds ratio [OR] 9.2, 95% confidence interval [CI] 3.3, 25.6) and morbidity (asphyxia: OR 5.7, 95% CI 4.5, 7.3; brachial plexus injury: OR 33.9, 95% CI 15.2, 76.1; and birth trauma: OR 5.8, 95% CI 4.7, 7.1) compared with breech delivery by prelabor cesarean in nulliparous women. In breech-presenting women with one prior vaginal delivery, neonatal mortality was not different between groups, but morbidities (asphyxia: OR 3.9, 95% CI 3.0, 5.1; brachial plexus injury: OR 22.4, 95% CI 9.9, 50.5; and birth trauma: OR 4.2, 95% CI 3.4, 5.3) remained increased for vaginal compared with cesarean delivery. CONCLUSION: The "normal" term breech fetus, when delivered vaginally, had significantly increased neonatal mortality (in nulliparous women) and morbidity (all breech deliveries), when compared with the breech fetus delivered by cesarean, which suggests that these patients might best be delivered by cesarean to avoid these adverse outcomes.

Prenatal diagnosis of omphalocele and left atrial isomerism (polysplenia) including complex congenital heart disease with ventricular noncompaction cardiomyopathy.

We report prenatal diagnosis of a rare constellation of findings, including omphalocele and polysplenia (left atrial isomerism [LAI]) with cardiac malformations including ventricular noncompaction (VNC) cardiomyopathy. The heterotaxy syndromes (polysplenia or LAI and asplenia or right atrial isomerism) are rare syndromes in which organs that are usually asymmetric are abnormally symmetric or abnormally positioned. Complex congenital heart disease is frequently associated with heterotaxy, with the heart being substantially affected in both structure and orientation. Heterotaxy has also been occasionally associated with a rare type of cardiomyopathy: VNC, described by Feldt et al and Ozkutlu et al. Omphalocele is a relatively common birth defect that is due to failure of the abdominal wall to close in association with return of the bowel in the first trimester. We report a case in which all of these findings were present. The cardiac findings were previously included in a pathology series on LAI with VNC by Friedberg et al; however, to our knowledge, pre-natal diagnosis of this unique collection of findings has not been reported previously.